Cardiovascular diseases are the leading cause of morbidity and mortality in developed countries, and most cardiovascular events are primarily due to thrombosis. Use of the first approved oral anticoagulant, warfarin, is plagued by its slow vitamin K-dependent antagonism, by drug-drug interactions, and by drug-food interactions, which results in the need for continuous monitoring for accurate dosing. Other anticoagulants such as heparin and fondaparinux are available only by parenteral administration. Limitations of these agents have prompted extensive research for novel anticoagulants.
Factor Xa is a unique serine protease in the blood coagulation cascade in that it is poised at a common junction where it is activated by both the intrinsic (contact activation) and extrinsic (tissue factor) pathways. In contrast to the multifunctional role that thrombin plays in the cascade, factor Xa only converts prothrombin to thrombin but does not affect the existing level of circulating thrombin. It has been shown that factor Xa inhibitors can exhibit a reduced bleeding risk and offer a superior safety/efficacy profile with respect to thrombin inhibitors in preclinical animal models. Therefore, in the past decade, significant progress has been made in the discovery and development of selective and orally active small-molecule factor Xa inhibitors as anticoagulants for venous or arterial thromboembolism, e.g., prevention of postoperative deep venous thrombosis (DVT) and pulmonary embolism (PE), prevention of stroke during atrial fibrillation, and treatment of acute coronary syndrome (ACS), highlighted by the approval of rivaroxaban represented by chemical formula (B-I) in 2011 (US2003/153610) followed by very recent authorization of apixaban represented by chemical formula (B-II) in 2013 by US FDA (WO2003/049681).

Currently, the standard dose of rivaroxaban is 10 mg once a day for the prevention of venous thromboembolism (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery. However, the higher efficacy of rivaroxaban is associated with a higher bleeding tendency. The risk of major or fatal bleeding can not be underestimated in particular if the patient needs to prescribe the drug over a long-term period. Furthermore, rivaroxaban has limited water solubility, consequently, it is difficult to develop intravenous formulations.
Difference with Rivaroxaban, the standard dose of apixaban is 5 mg twice a day. Apixaban is rapidly absorbed, reaching Cmax approximately 1-3 hours after administration. After reaching the initial Cmax, the plasma apixaban concentration shows an initial rapid decline and then a more gradual terminal phase, with a mean elimination t½ of 8-15 hours, and apixaban is therefore given twice daily. Apixaban is oxidized to several metabolites and these metabolites are excreted by multiple elimination pathways, including renal and intestinal excretion and metabolism. Concomitant treatment with potent inhibitors of CYP3A4 is contraindicated in apixaban-treated patients. Consequently, improvement in this regard considerably requires wider use of factor Xa inhibitors.
In this regard, great attention has been directed, from a clinical point of view, toward the development of a drug which is highly specific and potent inhibitor for factor Xa, which is more water-soluble, which is more effective in oral administration, more suitable for intravenous administration, and larger therapeutic windows and less bleeding tendency.